fluoroethyl)-L-tyrosine Research Articles

Photopenic defects on O-(2-[18F]-fluoroethyl)-L-tyrosine PET: clinical relevance in glioma patients.

O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET has a sensitivity of more than 90% to detect gliomas. In the remaining small fraction of gliomas without increased tracer uptake, some tumors even show photopenic defects whose clinical significance is unclear. Glioma patients with a negative FET PET scan prior to neuropathological confirmation were identified retrospectively. Gliomas were rated visually as (i) having indifferent FET uptake or (ii) photopenic, if FET uptake was below background activity. FET uptake in the area of signal hyperintensity on the T2/fluid attenuated inversion recovery-weighted MRI was evaluated by mean standardized uptake value (SUV) and mean tumor-to-brain ratio (TBR). The progression-free survival (PFS) of photopenic gliomas was compared with that of gliomas with indifferent FET uptake. Of 100 FET-negative gliomas, 40 cases with photopenic defects were identified. Fifteen of these 40 cases (38%) had World Health Organization (WHO) grades III and IV gliomas. FET uptake in photopenic gliomas was significantly decreased compared with both the healthy-appearing brain tissue (SUV, 0.89 ± 0.26 vs 1.08 ± 0.23; P < 0.001) and gliomas with indifferent FET uptake (TBR, 0.82 ± 0.09 vs 0.96 ± 0.13; P < 0.001). Irrespective of the applied treatment, isocitrate dehydrogenase (IDH)-mutated WHO grade II diffuse astrocytoma patients with indifferent FET uptake (n = 25) had a significantly longer PFS than patients with IDH-mutated diffuse astrocytomas (WHO grade II) with photopenic defects (n = 11) (51 vs 24 mo; P = 0.027). The multivariate survival analysis indicated that photopenic defects predict an unfavorable PFS (P = 0.009). Photopenic gliomas in negative FET PET scans should be managed more actively, as they seem to have a higher risk of harboring a higher-grade glioma and an unfavorable outcome.

178P - Feasibility of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for treatment monitoring of brain metastases in lung cancer patients

178P - Feasibility of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for treatment monitoring of brain metastases in lung cancer patients

Prognostic value of subventricular zone involvement in relation to tumor volumes defined by fused MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET imaging in glioblastoma multiforme

BackgroundSubventricular zone (SVZ) involvement is associated with a dismal prognosis in patients with glioblastoma multiforme (GBM). Dual-time point (dtp) O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET/CT (PET) may be a time- and cost-effective alternative to dynamic FET PET, but its prognostic value, particularly with respect to SVZ involvement, is unknown.MethodsThirty-five patients had two scans 5–15 and 50–60 min after i.v. FET injection to define tumor volumes and SVZ involvement before starting radiotherapy. Associations between clinical progression markers, MRI- and dtp FET PET-based tumor volumes, or SVZ involvement and progression-free (PFS) and overall survival (OS) were assessed in univariable and multivariable analyses.ResultsThe extent of resection was not related to outcomes. Albeit non-significant, dtp FET PET detected more SVZ infiltration than MRI (60% vs. 51%, p = 0.25) and was significantly associated with poor survival (p < 0.03), but PET-T1-Gad volumes were larger in this group (p < 0.002). Survival was shorter in patients with larger MRI tumor volumes, larger PET tumor volumes, and worse Karnofsky performance status (KPS), with fused PET-T1-Gad and KPS significant in multivariable analysis (p < 0.03). Uptake kinetics was not associated with treatment outcomes.ConclusionsFET PET-based tumor volumes may be useful for predicting worse prognosis glioblastoma. Although the presence of SVZ infiltration is linked to higher PET/MRI-based tumor volumes, the independent value of dtp FET PET parameters and SVZ infiltration as prognostic markers pre-irradiation has not been confirmed.

Predicting IDH genotype in gliomas using FET PET radiomics

Mutations in the isocitrate dehydrogenase (IDH mut) gene have gained paramount importance for the prognosis of glioma patients. To date, reliable techniques for a preoperative evaluation of IDH genotype remain scarce. Therefore, we investigated the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET radiomics using textural features combined with static and dynamic parameters of FET uptake for noninvasive prediction of IDH genotype. Prior to surgery, 84 patients with newly diagnosed and untreated gliomas underwent FET PET using a standard scanner (15 of 56 patients with IDH mut) or a dedicated high-resolution hybrid PET/MR scanner (11 of 28 patients with IDH mut). Static, dynamic and textural parameters of FET uptake in the tumor area were evaluated. Diagnostic accuracy of the parameters was evaluated using the neuropathological result as reference. Additionally, FET PET and textural parameters were combined to further increase the diagnostic accuracy. The resulting models were validated using cross-validation. Independent of scanner type, the combination of standard PET parameters with textural features increased significantly diagnostic accuracy. The highest diagnostic accuracy of 93% for prediction of IDH genotype was achieved with the hybrid PET/MR scanner. Our findings suggest that the combination of conventional FET PET parameters with textural features provides important diagnostic information for the non-invasive prediction of the IDH genotype.

Correlation of Dynamic O-(2-[18F]Fluoroethyl)-L-Tyrosine Positron Emission Tomography, Conventional Magnetic Resonance Imaging, and Whole-Brain Histopathology in a Pretreated Glioblastoma: A Postmortem Study

Amino acid positron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) provides important additional information on the extent of viable tumor tissue of glioblastoma compared with magnetic resonance imaging (MRI). Especially after radiochemotherapy, progression of contrast enhancement in MRI is equivocal and may represent either tumor progression or treatment-related changes. Here, the first case comparing postmortem whole-brain histology of a patient with pretreated glioblastoma with dynamic invivo FET PET and MRI is presented. A 61-year-old patient with glioblastoma initially underwent partial tumor resection and died 11 weeks after completion of chemoradiation with concurrent temozolomide. Three days before the patient died, a follow-up FET PET and MRI scan indicated tumor progression. Autopsy was performed 48 hours after death. After formalin fixation, a 7-cm bihemispherical segment of the brain containing the entire tumor mass was cut into 3500 consecutive 20μm coronal sections. Representative sections were stained with hematoxylin and eosin stain, cresyl violet, and glial fibrillary acidic protein immunohistochemistry. An experienced neuropathologist identified areas of dense and diffuse neoplastic infiltration, astrogliosis, and necrosis. Invivo FET PET, MRI datasets, and postmortem histology were co-registered and compared by 3 experienced physicians. Increased uptake of FET in the area of equivocal contrast enhancement on MRI correlated very well with dense infiltration by vital tumor cells and showed tracer kinetics typical for malignant gliomas. An area of predominantly reactive astrogliosis showed only moderate uptake of FET and tracer kinetics usually observed in benign lesions. This case report impressively documents the correct imaging of a progressive glioblastoma by FET PET.

The diagnostic accuracy of detecting malignant transformation of low-grade glioma using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography: a retrospective study.

The diagnostic accuracy of O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET scanning in detecting the malignant transformation of low-grade gliomas (LGGs) is controversial. In this study, the authors retrospectively assessed the diagnostic potential of FET PET in patients with MRI-suspected malignant progression of LGGs that had previously been treated and the relationship between FET uptake and MRI and molecular biomarkers. Forty-two patients who had previously undergone surgical or multimodal treatment for a histologically verified LGG were referred for FET PET assessment because of clinical signs and/or MRI findings suggestive of tumor progression. Maximal and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) on FET PET as well as kinetic FET PET parameters (time to peak [TTP] and time-activity curve [TAC]) were determined. Final diagnoses were confirmed histologically. The diagnostic accuracy of FET parameters, separately and combined, for the detection of malignant progression was evaluated using receiver operating characteristic (ROC) curve analysis. Possible predictors that might influence the diagnostic accuracy of FET PET were assessed using multiple linear regression analysis. Spearman’s rank correlation r method was applied to determine the correlation between TBRmax and TAC, and molecular biomarkers from tumor tissues. A total of 47 FET PET scans were obtained and showed no significant association between FET parameters and contrast enhancement on MRI. ROC curve analyses overall were unable to demonstrate any significant differentiation between nontransformed LGGs and LGGs that had transformed to high-grade gliomas when evaluating FET parameters separately or combined. After excluding the oligodendroglial subgroup, a significant difference was observed between nontransformed and transformed LGGs when combining FET parameters (i.e., TBRmax > 1.6, TAC describing a plateau or decreasing pattern, and TTP < 25 minutes), with the best result yielded by a combined analysis of TBRmax > 1.6 and TAC with a plateau or decreasing pattern (sensitivity 75% and specificity 83%, p = 0.003). The difference was even greater when patients who had previously undergone oncological treatment were also excluded (sensitivity 93% and specificity 100%, p = 0.001). Multiple linear regression analysis revealed that the presence of an oligodendroglial component (p = 0.029), previous oncological treatment (p = 0.039), and the combined FET parameters (p = 0.027) were significant confounding factors in the detection of malignant progression. TBRmax was positively correlated with increasing cell density (p = 0.040) and inversely correlated with IDH1 mutation (p = 0.006). A single FET PET scan obtained at the time of radiological and/or clinical progression seems to be of limited value in distinguishing transformed from nontransformed LGGs, especially if knowledge of the primary tumor histopathology is not known. Therefore, FET PET imaging alone is not adequate to replace histological confirmation, but it may provide valuable information on the location and delineation of active tumor tissue, as well as an assessment of tumor biology in a subgroup of LGGs.

Combined FET PET/MRI radiomics differentiates radiation injury from recurrent brain metastasis.

BackgroundThe aim of this study was to investigate the potential of combined textural feature analysis of contrast-enhanced MRI (CE-MRI) and static O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation between local recurrent brain metastasis and radiation injury since CE-MRI often remains inconclusive.MethodsFifty-two patients with new or progressive contrast-enhancing brain lesions on MRI after radiotherapy (predominantly stereotactic radiosurgery) of brain metastases were additionally investigated using FET PET. Based on histology (n = 19) or clinicoradiological follow-up (n = 33), local recurrent brain metastases were diagnosed in 21 patients (40%) and radiation injury in 31 patients (60%). Forty-two textural features were calculated on both unfiltered and filtered CE-MRI and summed FET PET images (20–40 min p.i.), using the software LIFEx. After feature selection, logistic regression models using a maximum of five features to avoid overfitting were calculated for each imaging modality separately and for the combined FET PET/MRI features. The resulting models were validated using cross-validation. Diagnostic accuracies were calculated for each imaging modality separately as well as for the combined model.ResultsFor the differentiation between radiation injury and recurrence of brain metastasis, textural features extracted from CE-MRI had a diagnostic accuracy of 81% (sensitivity, 67%; specificity, 90%). FET PET textural features revealed a slightly higher diagnostic accuracy of 83% (sensitivity, 88%; specificity, 75%). However, the highest diagnostic accuracy was obtained when combining CE-MRI and FET PET features (accuracy, 89%; sensitivity, 85%; specificity, 96%).ConclusionsOur findings suggest that combined FET PET/CE-MRI radiomics using textural feature analysis offers a great potential to contribute significantly to the management of patients with brain metastases.

18F]fluoroethyltyrosine-induced Cerenkov Luminescence Improves Image-Guided Surgical Resection of Glioma.

The extent of surgical resection is significantly correlated with outcome in glioma; however, current intraoperative navigational tools are useful only in a subset of patients. We show here that a new optical intraoperative technique, Cerenkov luminescence imaging (CLI) following intravenous injection of O‑(2-[18F]fluoroethyl)-L-tyrosine (FET), can be used to accurately delineate glioma margins, performing better than the current standard of fluorescence imaging with 5-aminolevulinic acid (5-ALA).Methods: Rats implanted orthotopically with U87, F98 and C6 glioblastoma cells were injected with FET and 5-aminolevulinic acid (5-ALA). Positive and negative tumor regions on histopathology were compared with CL and fluorescence images. The capability of FET CLI and 5-ALA fluorescence imaging to detect tumor was assessed using receptor operator characteristic curves and optimal thresholds (CLIOptROC and 5-ALAOptROC) separating tumor from healthy brain tissue were determined. These thresholds were used to guide prospective tumor resections, where the presence of tumor cells in the resected material and in the remaining brain were assessed by Ki-67 staining.Results: FET CLI signal was correlated with signal in preoperative PET images (y = 1.06x - 0.01; p < 0.0001) and with expression of the amino acid transporter SLC7A5 (LAT1). FET CLI (AUC = 97%) discriminated between glioblastoma and normal brain in human and rat orthografts more accurately than 5-ALA fluorescence (AUC = 91%), with a sensitivity >92% and specificity >91%, and resulted in a more complete tumor resection.Conclusion: FET CLI can be used to accurately delineate glioblastoma tumor margins, performing better than the current standard of fluorescence imaging following 5-ALA administration, and is therefore a promising technique for clinical translation.

Abstract 1869: Improved image-guided surgical resection of glioblastoma with [18F]-fluoroethyltyrosine Cerenkov luminescence imaging

Abstract The ability of a surgeon to completely resect a tumor is directly related to outcome in high- and low-grade gliomas. However current intraoperative navigational tools are useful only in a subset of glioma patients and do not detect the full extent of disease. We modelled orthotopic brain tumors by stereotactically implanting human U87, rat F98 and C6 glioblastoma cells into the forebrains of rats. We show here that a new hybrid PET-Cerenkov luminescence imaging approach using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) can accurately delineate tumor margins pre- and intra-operatively. We demonstrate consistency in the successful localisation and quantification of tumor burden using PET and Cerenkov luminescence imaging. The Cerenkov signal in individual tumors was directly proportional to the signal detected in corresponding FET PET scans (y = 1.06x - 0.01; R2 = 0.98; p &amp;lt; 0.0001) and subsequent autoradiography indicated equivalence between modalities. Cerenkov luminescence was better able to discriminate tumor from healthy brain tissue than the current ‘gold standard’ for intraoperative mapping, 5-ALA (5-aminolevulinic acid), indicated by a greater area under the ROC curve in human xenograft (0.968 ± 0.003 vs. 0.893 ± 0.019; p = 0.003) and syngeneic rat glioma models (0.970 ± 0.010 vs. 0.774 ± 0.046; p = 0.006). The quantitative accuracy of Cerenkov luminescence enabled us to determine a threshold of 2.1 x 102 p-1 sec-1 cm-2 sr-1 MBq-1 that separated U87 human glioblastoma and normal brain tissue, more precisely guiding tumor excision than 5-ALA. At the optimal threshold the specificity for detecting syngeneic rat and human xenograft gliomas was better with FET Cerenkov than 5-ALA (91.1 ± 2.7 % vs. 67.2 ± 5.2 %; p = 0.007 and 91.2 ± 1.0 % vs. 82.9 ± 1.8 %; p = 0.005 respectively). We confirmed and extended these findings at higher spatial resolution on cryosections using FET autoradiography and 5-ALA confocal microscopy, with FET demonstrating higher specificity and sensitivity for tumor detection than 5-ALA. FET PET-Cerenkov luminescence imaging has the potential for guiding resections in a much broader range of glioma patients than current approaches. Previous clinical experience with FET offers a facile route for clinical translation of this technology. Citation Format: David Y. Lewis, Richard Mair, Alan J. Wright, Kieren Allinson, Scott K. Lyons, Tom Booth, Robert Bielik, Dmitry Soloviev, Kevin M. Brindle. Improved image-guided surgical resection of glioblastoma with [18F]-fluoroethyltyrosine Cerenkov luminescence imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1869. doi:10.1158/1538-7445.AM2017-1869

Imaging of amino acid transport in brain tumours: Positron emission tomography with O-(2-[18F]fluoroethyl)-L-tyrosine (FET).

The assessment of cerebral gliomas using magnetic resonance imaging (MRI) provides excellent structural images but cannot solve all diagnostic problems satisfactorily. The differentiation of tumour tissue from non-neoplastic changes may be difficult especially in the post-treatment phase. In recent years, positron emission tomography (PET) using radiolabelled amino acids has gained considerable interest as an additional tool to improve the diagnosis of cerebral gliomas and brain metastases. A key step for this advancement was the development of the F-18 labelled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) which has spread rapidly in the last decade and replaced carbon-11 labelled amino acid tracers such as 11C-methyl-L-methionine (MET) in many centres in Europe. FET can be produced with high efficiency and distributed in a satellite concept like 2-[18F]fluoro-2-deoxy-D-glucose (FDG). Furthermore, FET exhibits favourable properties such as high in vivo stability, high tumour to background contrast and tissue specific tracer kinetics, which provides additional information for tumour grading or differential diagnosis. The Response Assessment in Neuro-Oncology (RANO) working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recently recommended the additional use of amino acid PET imaging for brain tumour management. FET PET can provide important diagnostic information in crucial situations such as the definition of biopsy site, the delineation of cerebral gliomas for therapy planning, sensitive monitoring of treatment response and an improved differentiation of tumour recurrence from treatment-related changes. In this article the basic information, methodological aspects and the actual status of clinical application of FET PET are reviewed.

Patterns of failure for patients with glioblastoma following O-(2-[18F]fluoroethyl)-L-tyrosine PET- and MRI-guided radiotherapy

Background and purposeTo evaluate the patterns of failure following clinical introduction of amino-acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET-guided target definition for radiotherapy (RT) of glioblastoma patients. Materials and methodsThe first 66 consecutive patients with confirmed histology, scanned using FET-PET/CT and MRI were selected for evaluation. Chemo-radiotherapy was delivered to a volume based on both MRI and FET-PET (PETvol). The volume of recurrence (RV) was defined on MRI data collected at the time of progression according to RANO criteria. ResultsFifty patients were evaluable, with median follow-up of 45months. Central, in-field, marginal and distant recurrences were observed for 82%, 10%, 2%, and 6% of the patients, respectively. We found a volumetric overlap of 26%, 31% and 39% of the RV with the contrast-enhancing MR volume, PETvol and the composite MRPETvol, respectively. MGMT-methylation (p=0.03), larger PETvol (p<0.001), and less extensive surgery (p<0.001), were associated with larger PETvol overlap. ConclusionThe combined MRPETvol had a stronger association with the recurrence volume than either of the modalities alone. Larger overlap of PETvol and RV was observed for patients with MGMT-methylation, less extensive surgery, and large PETvol on the RT-planning scans.

Uptake of 18F-FET and 18F-FCH in Human Glioblastoma T98G Cell Line after Irradiation with Photons or Carbon Ions.

The differential diagnosis between recurrence of gliomas or brain metastases and this phenomenon is important in order to choose the best therapy and predict the prognosis but is still a big problem for physicians. The new emerging MRI, CT, and PET diagnostic modalities still lack sufficient accuracy. Radiolabeled choline and amino acids have been reported to show great tumor specificity. We studied the uptake kinetics of [18F]fluoromethyl-choline (FCH) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) by the T98G human glioblastoma cells from 20 to 120 min after irradiation either with photons at 2-10-20 Gy or with carbon ions at 2 Gy (at the National Centre for Oncological Hadrontherapy (CNAO), Pavia, Italy). We also evaluated the cell death and morphology changes induced by radiation treatment. Both FET and FCH are able to trace tumor behavior in terms of higher uptake for increased doses of radiation treatment, due to the upregulation of cells attempts to repair nonlethal damage. Our data suggest that both FCH and FET could be useful to analyze the metabolic pathways of glioblastoma cells before and after radiotherapy. Physicians will have to consider the different kinetics pathways of uptake concerning the two radiopharmaceuticals.

The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy.

Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers 11C-methyl-l-methionine (MET), O-(2-[18F]fluoroethyl)-l-tyrosine (FET) and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.

PET/MRI and brain tumors: focus on radiation oncology treatment planning

In brain tumors, imaging by magnetic resonance imaging (MRI) can very accurately visualize anatomy and morphology of healthy and malignant tissue, but neither contrast-enhancing areas in T1-weighted sequences, nor hyperintensities in T2/FLAIR sequences are specific for tumor tissue, especially when considering the manifold alterations resulting from previous treatment. Imaging the biology of tumor tissue by positron emission tomography (PET), therefore, is a highly interesting approach to improve the detection of macroscopic tumor which is the prerequisite for high-precision radiotherapy treatment planning. This review will focus on the benefits of amino acid tracers (l-[methyl-11C]methionine (MET) and O-(2-[18F]fluoroethyl)-l-tyrosine (FET)) in neurooncology and their implementation in radiation oncology. Furthermore, a brief overview of the current impact of 2-deoxy-2-(18F)fluoro-d-glucose (FDG), nucleic acid analogs, hypoxia tracers, and Somatostatin receptor (SSTR) analogs on radiotherapy planning in brain tumors is provided. Among advances in multiparametric MRI, Diffusion-weighted imaging (DWI) has attracted particular attention since it can predict prognosis, as well as indicate response to treatment and has already been introduced into target volume definition for radiotherapy of various cancers (e.g., prostate and rectal cancer). Additionally, advances in MR spectroscopy (MRS) are mentioned. Finally, these findings will be discussed concerning their influence on current aspects of integrated PET/MR hybrid imaging.

(18)F-FET-PET in Primary Hyperparathyroidism: A Pilot Study.

Preoperative localisation of the diseased parathyroid gland(s) in primary hyperparathyroidism (PHP) is a prerequisite for subsequent minimally invasive surgery. Recently, as alternatives to conventional sestamibi parathyroid scintigraphy, the 11C-based positron emission tomography (PET) tracers methionine and choline have shown promise for this purpose. We evaluated the feasibility of using the 18F-based PET tracer fluoroethyl-l-tyrosine (FET), as the longer half-life of 18F makes it logistically more favourable. As a proof-of-concept study, we included two patients with PHP in which dual-isotope parathyroid subtraction single photon emission computed tomography had determined the exact location of the parathyroid adenoma. A dynamic FET PET/CT scan was performed with subsequent visual evaluation and calculation of target-to-background (TBR; parathyroid vs. thyroid). The maximum TBR in the two patients under study was achieved approximately 30 min after the injection of the tracer and was 1.5 and 1.7, respectively. This ratio was too small to allow for confident visualisation of the adenomas. FET PET/CT seems not feasible as a preoperative imaging modality in PHP.

Textural analysis of pre-therapeutic [18F]-FET-PET and its correlation with tumor grade and patient survival in high-grade gliomas.

Amino acid positron emission tomography (PET) with [18F]-fluoroethyl-L-tyrosine (FET) is well established in the diagnostic work-up of malignant brain tumors. Analysis of FET-PET data using tumor-to-background ratios (TBR) has been shown to be highly valuable for the detection of viable hypermetabolic brain tumor tissue; however, it has not proven equally useful for tumor grading. Recently, textural features in 18-fluorodeoxyglucose-PET have been proposed as a method to quantify the heterogeneity of glucose metabolism in a variety of tumor entities. Herein we evaluate whether textural FET-PET features are of utility for grading and prognostication in patients with high-grade gliomas. One hundred thirteen patients (70men, 43women) with histologically proven high-grade gliomas were included in this retrospective study. All patients received static FET-PET scans prior to first-line therapy. TBR (max and mean), volumetric parameters and textural parameters based on gray-level neighborhood difference matrices were derived from static FET-PET images. Receiver operating characteristic (ROC) and discriminant function analyses were used to assess the value for tumor grading. Kaplan-Meier curves and univariate and multivariate Cox regression were employed for analysis of progression-free and overall survival. All FET-PET textural parameters showed the ability to differentiate between World Health Organization (WHO) grade III and IV tumors (p < 0.001; AUC 0.775). Further improvement in discriminatory power was possible through a combination of texture and metabolic tumor volume, classifying 85% of tumors correctly (AUC 0.830). TBR and volumetric parameters alone were correlated with tumor grade, but showed lower AUC values (0.644 and 0.710, respectively). Furthermore, a correlation of FET-PET texture but not TBR was shown with patient PFS and OS, proving significant in multivariate analysis as well. Volumetric parameters were predictive for OS, but this correlation did not hold in multivariate analysis. Determination of uptake heterogeneity in pre-therapeutic FET-PET using textural features proved valuable for the (sub-)grading of high-grade glioma as well as prediction of tumor progression and patient survival, and showed improved performance compared to standard parameters such as TBR and tumor volume. Our results underscore the importance of intratumoral heterogeneity in the biology of high-grade glial cell tumors and may contribute to individual therapy planning in the future, although they must be confirmed in prospective studies before incorporation into clinical routine.

From the clinician's point of view - What is the status quo of positron emission tomography in patients with brain tumors?

The most common type of primary brain tumor is malignant glioma. Despite intensive therapeutic efforts, the majority of these neoplasms remain incurable. Imaging techniques are important for initial tumor detection and comprise indispensable tools for monitoring treatment. Structural imaging using contrast-enhanced MRI is the method of choice for brain tumor surveillance, but its capacity to differentiate tumor from nonspecific tissue changes can be limited, particularly with posttreatment gliomas. Metabolic imaging using positron-emission-tomography (PET) can provide relevant additional information, which may allow for better assessment of tumor burden in ambiguous cases. Specific PET tracers have addressed numerous molecular targets in the last decades, but only a few have achieved relevance in routine clinical practice. At present, PET studies using radiolabeled amino acids appear to improve clinical decision-making as these tracers can offer better delineation of tumor extent as well as improved targeting of biopsies, surgical interventions, and radiation therapy. Amino acid PET imaging also appears useful for distinguishing glioma recurrence or progression from postradiation treatment effects, particularly radiation necrosis and pseudoprogression, and provides information on histological grading and patient prognosis. In the last decade, the tracers O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) and 3,4-dihydroxy-6-[(18)F]-fluoro-L-phenylalanine (FDOPA) have been increasingly used for these indications. This review article focuses on these tracers and summarizes their recent applications for patients with brain tumors. Current uses of tracers other than FET and FDOPA are also discussed, and the most frequent practical questions regarding PET brain tumor imaging are reviewed.

Adapting MR-BrainPET scans for comparison with conventional PET: experiences with dynamic FET-PET in brain tumours

Imaging results from subsequent measurements (preclinical 3T MR-BrainPET, HR+) are compared. O-(2-[18F]fluoroethyl)-L-tyrosine (FET) may exhibit non-uniform tracer uptake in gliomas. The aim was to analyse and adapt the physical properties of the scanners and study variations of biological tumour volume (BTV) in early and late FET-PET. Spatial resolution of the BrainPET and HR+ was measured according to NEMA standard. For evaluation of a threshold-based volume determination -as used for BTV- volumes of an 18F-filled spheres phantom were evaluated. Influence of different filter kernels for correction of differences in spatial resolution hereon was compared. Differences in BTV between early and late FET-PET of 45 patients were analysed. BTV was determined using a tumour-to-brain ratio ≥1.6 [1]. Spatial resolution (FWHM) of the BrainPET was 2.63mm–3.47mm and 4.39mm–5.10mm for the HR+ (10mm off-centre) [2]. 3D-filtered backprojection was used for reconstruction [3]. BTV of largest sphere was 22.8ml in HR+ and between 23.2ml (unfiltered) and 24.5ml (3D-Gaussian 3.5mm) in the BrainPET. BTV of smallest sphere was 0.1 ml in HR+ and between 0.2ml (unfiltered) and 0.06ml (3D-Gaussian 3.5mm) in the BrainPET. A 2.5mm filter showed the smallest deviation for all spheres and was applied to the BrainPET data for cross-scanner comparison. Changes in BTV >10% were considered significant and not related to physical differences between scanners. 41% of patients showed a considerable deviation between early and late FET-PET. BTV increased in 14 patients. Four patients showed a FET positive region only in late FET-PET. Taking into account the physical differences of PET scanners is important for cross-scanner studies. It was shown in a patient study that BTV may vary between early and late FET-PET, which is important for patient management and needs further investigation. Figure 1 MRI and FET-PET scan of a patient with oligodendroglioma WHO grade II. T1-weighted MR image (MPRAGE) acquired simultaneously to the early PET scan with the 3T MR-BrainPET (top). Summation scan 20-40 min post-injection (BrainPET, middle), summation scan ...

Imaging the L-Type Amino Acid Transporter-1 (LAT1) with Zr-89 ImmunoPET

The L-type amino acid transporter-1 (LAT1, SLC7A5) is upregulated in a wide range of human cancers, positively correlated with the biological aggressiveness of tumors, and a promising target for both imaging and therapy. Radiolabeled amino acids such as O-(2-[18F]fluoroethyl)-L-tyrosine (FET) that are transport substrates for system L amino acid transporters including LAT1 have met limited success for oncologic imaging outside of the brain, and thus new strategies are needed for imaging LAT1 in systemic cancers. Here, we describe the development and biological evaluation of a novel zirconium-89 labeled antibody, [89Zr]DFO-Ab2, targeting the extracellular domain of LAT1 in a preclinical model of colorectal cancer. This tracer demonstrated specificity for LAT1 in vitro and in vivo with excellent tumor imaging properties in mice with xenograft tumors. PET imaging studies showed high tumor uptake, with optimal tumor-to-non target contrast achieved at 7 days post administration. Biodistribution studies demonstrated tumor uptake of 10.5 ± 1.8 percent injected dose per gram (%ID/g) at 7 days with a tumor to muscle ratio of 13 to 1. In contrast, the peak tumor uptake of the radiolabeled amino acid [18F]FET was 4.4 ± 0.5 %ID/g at 30 min after injection with a tumor to muscle ratio of 1.4 to 1. Blocking studies with unlabeled anti-LAT1 antibody demonstrated a 55% reduction of [89Zr]DFO-Ab2 accumulation in the tumor at 7 days. These results are the first report of direct PET imaging of LAT1 and demonstrate the potential of immunoPET agents for imaging specific amino acid transporters.

Fluorescein sodium in brain tumor surgery – Response

Dear Editor, We would like to thank Florian Stockhammer [10] and Ricardo Diez Valle [3] for their comments on our manuscript, "Sodium fluorescein-guided resection under the YELLOW 560 nm surgical microscope filter in malignant brain tumor surgery – a feasibility study" [9]. Because of the similarity of Diez Valle’s and Stockhammer’s criticism of our scientific approach, we take the liberty of addressing their comments in one single response: Our study─ in terms of an off-label use (ethic vote 12-1010215) ─ exclusively dealt with the subject of the technical feasibility of intraoperative fluorescence due to the injection of fluorescein sodium and the application of the newly developed surgical microscope filter YELLOW 560 nm in malignant intracranial tumors. To illustrate the surgeon’s subjective assessment of the fluorescent effect, we deliberately chose the termini "helpful" and "not helpful", because we explicitly wanted to avoid the impression that the evaluation of the fluorescent effect in the tumor area was validated to a referencing scale─a method recommended by Diez Valle. We purposely did not present any detailed assessment protocol of, for instance, possible side effects of fluorescein sodium, because this dye has already been used in even higher doses in ophthalmic surgery for some 40 years [6]. Such analyses maybe the goal of phase-II trials, but not of a feasibility study. Furthermore, we believe that the side effects of 5aminolevulinic acid (5-ALA) is common knowledge to the addressed audience. In contrast to Stockhammer’s statement, the fact that fluorescein sodium can be intraoperatively injected "on the fly" should be seen as an advantage. This type of application schedule guarantees flexibility during a surgical procedure which is not the case when using 5-ALA. Stockhammer has questioned the resection of contrastenhanced mass in MRI in the surgical removal of high-grade gliomas. He indicated that metabolic depiction using amino acid positron emission tomography (PET) imaging is the more feasible approach. The papers cited in the article to support this statement indicate that O-(2-[18F]Fluoroethyl)-L-tyrosine (FET )PET can be useful for the detection of anaplastic foci within gliomas, and that 5-ALA uptake correlated to PET findings. To our best knowledge, resection of the contrast enhancing mass [T1-weighted, contrast enhanced magnetic resonance imaging (MRI)] still is the benchmark for the resection of glioblastomas (GBM) [2]. It has not been established yet that PET-guided surgery has added any clinical benefit to GBM patients. In contrast, a recent study has shown that ALA-uptake exceeded the area of tracer uptake in amino acid PET [7]. A recent review article by Orringer et al. [5] is still based on MRI imaging for the analysis of radiographically determined extent of resection (EOR). Whether amino acid PETcan be pronounced as new gold standard for the resection of malignant gliomas still remains an open question. The major critique byDiez Valle and Stockhammer referred to the EOR. We would like to address this issue in detail: